The long-term objective of this proposal is to identify the cellular mechanisms that regulate inhibitory synapse function during development and following hearing loss. The research plan is divided into three areas: (1) The regulation of inhibitory synapse strength will be studied in the developing gerbil lateral superior olivary nucleus (LSO), using a brain slice preparation. The activity-dependent depression of inhibitory synapses from the medial nucleus of the trapezoid body (MNTB) to the LSO will be examined with whole-cell voltage-clamp recordings. The relationship between depression and inhibitory synapse refinement will be tested with paired recordings from dye-filled MNTB and LSO neurons. The cellular basis for depression will be examined by direct activation or blockade of GABA and glycine receptors, and the use of transgenic receptor deletions in mice. The postsynaptic signalling pathway that induces depression will be tested by intracellular application of kinase and phosphatase antagonists. (2) The affect of deafness on inhibitory synapse function will be examined in the gerbil inferior colliculus. Using a brain slice preparation, gramicidin perforated-patch recordings will be obtained from IC neurons, and the evoked synaptic currents will be monitored in response to lemnisal or commissural stimulation. To determine why inhibitor synapse reversal potential depolarizes in deafened animals, postsynaptic chloride homeostasis will be examined in normal and deafened animals using chloride pump and voltage-gated chloride channel antagonists. The ability of synaptic activity to regulate chloride homeostasis will be assessed by monitoring inhibitory reversal potential before and after a prolonged period of excitatory or inhibitory activity. (3) The in vivo occurrence of inhibitory synaptic plasticity will be examined wit extracellular recordings from juvenile gerbils during sound stimulation. The strength of sound evoked inhibition in the LSO will be assessed before and after coactivation of excitatory and inhibitory pathways, using stimulus patterns that induce inhibitory depression in the LSO brain slice. To determine whether inhibitory synaptic strength declines in LSO following deafferentation, the inhibitory pathway will be stimulated electrically following cochlear ablation. The proposed experiments will demonstrate how inhibitory synapse physiology can be modified in the central auditory system, and suggest how inhibitory dysfunction could affect acoustic processing following profound deafness.